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Pharmaceutical compositions comprising nilotinib or its salt

a technology which is applied in the direction of drug compositions, biocide, capsule delivery, etc., can solve the problems of difficult formulation and delivery of nilotinib and its salts, and poor water soluble compounds

Active Publication Date: 2010-04-08
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]The present invention provides for a novel pharmaceutical composition that comprises a therapeutic compound of formula I, for example, nilotinib or a salt thereof. The pharmaceutical compositions are in the form of solid oral dosage forms, especially capsules. The capsules are filled with granules of the therapeutic compound blended with an external phase comprising at least one pharmaceutically acceptable excipient. A particularly useful process for making the granules is a wet granulation process. The therapeutic compound and any pharmaceutically acceptable excipients, for example a surfactant, are wet massed with purified water (or organic solvents) and subsequently dried to form granules. An example of a particularly useful surfactant, is a poloxamer such as poloxamer 188. It has been found that the use of a surfactant allows for a decrease in concentration of other excipients (such as lubricants).

Problems solved by technology

Posing a challenge resolving this need is the physiochemical properties of such therapeutic compounds.
Nilotinib and its salts are poorly water soluble compounds and are difficult to formulate and deliver (i.e., made bioavailable when ingested orally).

Method used

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  • Pharmaceutical compositions comprising nilotinib or its salt
  • Pharmaceutical compositions comprising nilotinib or its salt
  • Pharmaceutical compositions comprising nilotinib or its salt

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0071]The therapeutic compound in this example is nilotinib hydrochloride monohydrate. This therapeutic compound has low solubility in aqueous media. Furthermore this therapeutic compound has a slight hygroscopic tendency.

[0072]Table 1 shows the formulation of Example 1

Amount perPercentageIngredientscapsule (mg)(w % / w %)GranuleNilotinib hydrochloride220.6055.2%monohydratePoloxamer 1883.180.8Lactose monohydrate78.4719.6%Polyvinyl pyrrolidone15.91  4%External PhaseLactose monohydrate77.6419.4%Colloidal silicon dioxide2.10 0.5%magnesium stearate2.10 0.5%Total400.0

[0073]The nilotinib hydrochloride monohydrate, lactose monohydrate and polyvinyl pyrrolidone are mixed together using a high shear mixer to form a powder blend. The poloxamer 188 is solubilized with purified water and then added to the powder blend in order to wet the powder blend. Then, the mixture is kneaded and dried in a fluid bed dryer to form granules. Lactose monohydrate and colloidal silicon dioxide (as part of the ext...

example 2

Dissolution Profile

[0076]Dissolution testing is performed using the basket method according to Ph. Eur. 2.9.3 ‘Dissolution test for solid dosage forms’ and USP ‘Dissolution’ at 100 rpm in 1000 ml 0.1 N HCL as dissolution material. The determination of the amount of drug substance dissolved (%) is performed with a UV detection method. The method has been validated for selectivity, accuracy, precision and linearity.

TABLE 2Dissolution Results of the Capsule of Example 1Time PointMean of Nilotinib hydrochloride(min)monohydrate dissolved in %529.81597.23098.56099.1

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Abstract

A pharmaceutical composition, especially capsules. comprising granules containing nilotinib or a salt thereof with at least one pharmaceutically acceptable excipient. The granules may be produced by a wet granulation process.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a pharmaceutical composition comprising a therapeutic compound of formula I (see below), for example nilotinib. Such a pharmaceutical composition may be prepared by a wet granulation process for preparing granules that are subsequently filled into a capsule.BACKGROUND OF THE INVENTION[0002]Nilotinib is 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl) -3-(trifluoromethyl)phenyl] benzamide. A particularly useful salt of nilotinib is nilotinib hydrochloride monohydrate. These therapeutic compounds have utility as inhibitors of the protein tyrosine kinase (TK) activity of Bcr-Abl. Examples of conditions that may be treated by such therapeutic compounds include, but are not limited to, chronic myeloid leukemia and gastrointestinal stromal tumors.[0003]There is a need to formulate nilotinib and the other therapeutic compounds hereinafter disclosed into pharmaceutical compositions, especially sol...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61P35/02A61P35/00
CPCA61K9/1617A61K9/1623A61K31/506A61K9/1641A61K9/1635A61P35/00A61P35/02A61P43/00A61K9/48A61K9/16
Inventor BRUNEAU, NATHALIE
Owner NOVARTIS AG
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